In adult humans, each of over a trillion neurons connects with on average over a thousand target cells (Tessier-Lavigne, M. et al. (1996) Science 274:1123-1133). These neuronal connections form during embryonic development. Each differentiating neuron sends out an axon tipped at the leading edge by a growth cone. Aided by molecular guidance cues, the growth cone migrates through the embryonic environment to its synaptic target.
The wiring of the nervous system occurs in a stepwise manner. The first axons to develop navigate through an axon-free environment when the embryo is still relatively small. However, most axons face an expanding environment crisscrossed by a scaffold of earlier projecting axons. Many later-developing axons travel along preexisting axon tracts (or fascicles) for at least some of their trajectory, and switch from one fascicle to another at specific points. This "selective fasciculation" strategy simplifies the assembly of large nervous systems such as those of humans. In these large nervous systems, axons extend to their targets in successive waves over a period of several months (Tessier-Lavigne et al., supra).
Axon growth is guided in part by contact-mediated mechanisms involving cell surface and extracellular matrix (ECM) molecules. Many ECM molecules can act either as promoters or inhibitors of neurite outgrowth and extension (Tessier-Lavigne et al., supra). Receptors for ECM molecules include integrins, cellular adhesion molecules (CAMs), and proteoglycans. ECM molecules and their receptors have also been implicated in the adhesion, maintenance, and differentiation of neurons (Reichardt, L. F. et al. (1991) Ann. Rev. Neurosci 14:531-571).
In strains of C. elegans with locomotory defects known as uncoordinated or unc mutants, genes have been identified that, when mutated, affect axon growth along fascicles but not along non-neural substrates. Mutations in this fascicle-specific group of genes (unc-34, unc-71, and unc-76) cause two types of defects: many axons fail to extend fully within the axon bundles, and many axons fail to remain in their normal fascicles (McIntire, S. L. et al. (1992) Neuron 8:307-322). The unc-76 mutant strains show the most severe locomotion defects. Many of the axons in unc-76 mutants which grow abnormally in fascicles extend normally around the body wall, which suggests that unc-76 is necessary for axon-axon interactions (Bloom, L. et al. (1997) Proc. Natl. Acad. Sci. USA 94:3414-3419).
Expression of Unc-76 protein was observed throughout the C. elegans nervous system at all developmental stages from newly hatched larva through adult. Unc-76 was not found in non-neuronal cells (Bloom et al., supra). Unc-76 protein may play a structural role in the formation or maintenance of fascicles, possibly by association with a CAM, the axonal membrane, or the cytoskeleton. Unc-76 protein may also transduce signals from cell-surface molecules to the intracellular machinery that regulates axonal extension and adhesion (Bloom et al., supra).
Zygin-1 from rat brain, a homolog of Unc-76, was characterized as a synaptotagmin-binding protein (Sugita, S. et al. GenBank 1778068 and 1778069). Furthermore, Zeta-1 from rat brain, which is essentially identical to rat Zygin-1, was characterized as a protein kinase C-binding protein (Kuroda, S. et al. GenBank 1199670 and 1199671).
The discovery of a new human zygin-1 and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer and neuronal disorders.